Monoheteroring compounds and their use

ABSTRACT

Novel 2,4-diamino-5-(substituted naphthylmethyl)pyrimidines have been found to have superior antibacterial activity.

The present invention relates to novel2,4-diamino-5-(substituted)pyrimidines, to pharmaceutical compositionscontaining them, to processes for preparing them and their compositions,to intermediates for making them and to their use in the treatment ofmicrobial infections.

Certain 2,4-diamino-5-benzylpyrimidines have been demonstrated to bepotent inhibitors of dihydrofolate reductase (DHFR) which catalyses thereduction of dihydrofolic acid to tetrahydrofolic acid (THFA). Thisproperty has been shown frequently to result in useful pharmaceuticalproperties particularly in the treatment of bacterial infections. Thus,U.K. Patent Specification No. 875,562 discloses inter alia compounds ofthe formula (I): ##STR1## wherein R¹, R² and R³ are the same ordifferent C₁₋₄ alkoxy groups. Trimethoprim,2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidine, is specificallydisclosed in U.K. Pat. No. 875,562 and is the most active generalantibacterial agent amongst the 2,4-diamino-5-benzylpyrimidines known todate. Due to their mode of action, these benzylpyrimidines potentiatethe antibacterial activity of the sulphonamides and trimethoprim hasbeen used extensively over the last decade in human therapy incombination with various sulphonamides, and in particular withsulphamethoxazole, for the treatment of bacterial infections.

U.K. Patent Specification No. 957797 discloses inter alia2,4-diamino-5-(1-naphthylmethyl)pyrimidine which is described as havinguseful biological activity. Further investigation revealed that thiscompound was considerably inferior to trimethoprim.

Unfortunately, whilst trimethoprim has an excellent level of activityagainst most aerobic bacteria its activity against anaerobic bacteria isless impressive and its activity against certain aerobic bacteria couldbeneficially be improved upon. A novel group of2,4-diamino-5-substituted pyrimidines has now been found many of thecompounds having a general level of activity against aerobic bacteriacomparable to that of trimethoprim whilst having a superior level ofactivity against anaerobic bacteria. Some of these compounds are alsoconsiderably superior to trimethoprim against gram positive aerobicbacteria, particularly Staphylococcus aureus and some compounds have adifferent pharmacokinetic profile, for example, a longer half life, thantrimethoprim.

Accordingly, the present invention provides a compound of the formula(II): ##STR2## or a salt, N-oxide or acyl derivative thereof, whereinthe dotted line represent single or double bonds, R¹ and R² are the sameor different and each is hydrogen, halogen, C₁₋₄ alkyl, C₁₋₄ alkylthioor C₁₋₄ alkoxy, optionally substituted by halogen, hydroxy or C₁₋₂alkoxy or R¹ and R² are linked to the same carbon atom to form a groupC═O, ##STR3## R³ and R⁴ are the same or different and each is hydrogen,halogen, C₂₋₄ alkenyl, C₂₋₄ alkenyloxy, nitro, cyano, hydroxy, mercapto,a group --OSO₂ R⁷ or --S(O)_(n) R⁷ wherein R⁷ is C₁₋₃ alkyl and n is 0,1 or 2, a group --COR⁸ wherein R⁸ is methyl, ethyl, methoxy, ethoxy,amino, methylamino, ethylamino, dimethylamino, or diethylamino, or eachis amino optionally substituted by one or more C₁₋₄ alkyl or C₁₋₄ acylor the nitrogen atom forms part of a five or six membered heterocyclicring, C₁₋₄ alkyl or C₁₋₄ alkoxy each optionally substituted by halogen,hydroxy, or C₁₋₂ alkoxy, or R³ and R⁴ together form a methylenedioxygroup; except that when R¹, R² and R³ are all hydrogen R⁴ is neitherhydroxy nor hydrogen and R¹ and R² are not substituents other thanhydrogen on the carbon atom at the 8-position.

It will be readily apparent that R¹ will not be ═O, ═S, or gem dimethylwhen the compound of the formula (II) is a substituted2,4-diamino-5-naphthylmethylpyrimidine.

Particularly suitable compounds of the formula (II) include those of theformula (III): ##STR4## or a salt, N-oxide or acyl derivative thereofwherein the dotted lines, R¹ and R² are as hereinbefore defined and R⁹and R¹⁰ are the same or different and each is hydrogen, halogen, C₂₋₄alkenyl, C₂₋₃ alkenyloxy, nitro, a group NR¹¹ R¹² wherein R¹¹ and R¹²are the same or different and each is hydrogen, methyl or ethyl or NR¹¹R¹² forms a five or six-membered heterocyclic ring, cyano, hydroxy, agroup --S(O)_(n) R⁷ or COR⁸ as hereinbefore defined, or C₁₋₄ alkyl orC₁₋₄ alkoxy each optionally substituted by halogen, hydroxy or C₁₋₃alkoxy, except that R⁹ and R¹⁰ are not both hydrogen or halogen, thateither R¹ and R² are not substituents on the carbon atom at the8-position.

Suitably R⁹ is C₂₋₃ alkenyl, halogen, a group S(O)_(n) R⁷ ashereinbefore defined, cyano, amino, mono-C₁₋₃ -alkyl substituted amino,or C₁₋₃ alkyl or C₁₋₃ alkoxy each optionally substituted by halogen,hydroxy or C₁₋₃ alkoxy.

Most suitably R⁹ is methoxy, ethoxy, methoxyethoxy, methyl, ethyl,propyl, vinyl, allyl, propenyl, halogen, methylthio, ethylthio.Preferably R⁹ is methyl, methoxy or ethoxy, particularly methoxy.

Suitably R¹⁰ is hydrogen, hydroxy, amino, mono- or di-C₁₋₃ alkylsubstituted amino, nitro, cyano, pyrrolyl, a group --S(O)_(n) R⁷ or--COR⁸ as hereinbefore defined or R¹⁰ is C₁₋₃ alkoxy optionallysubstituted by halogen, hydroxy or C₁₋₃ alkoxy.

Most suitably R¹⁰ is hydrogen, hydroxy, methoxy, ethoxy, nitro, amino,methylamino, dimethylamino, ethylamino, diethylamino, methylthio,ethylthio or pyrrolyl. Preferably R¹⁰ is methoxy, amino, mono- ordimethylamino or methylthio, particularly methoxy, dimethylamino ormethylthio.

Preferably the dotted lines represent double bonds.

Suitably R¹ is hydrogen, gem dimethyl, C₁₋₃ alkyl optionally substitutedby halogen, C₁₋₃ -alkylthio or C₁₋₃ alkoxy optionally substituted byhalogen, hydroxy or C₁₋₂ alkoxy. Most suitably R¹ is hydrogen, methyl,trifluoromethyl or methoxy and preferably R¹ is hydrogen.

Suitably R² is hydrogen, C₁₋₃ alkyl, optionally substituted by halogen,C₁₋₃ -alkylthio or C₁₋₃ alkoxy optionally substituted by halogen,hydroxy or C₁₋₂ alkoxy. Most suitably R² is hydrogen, methyl,trifluoromethyl or methoxy and preferably R² is hydrogen.

One group of preferred compounds of the present invention includes thoseof the formula (IV): ##STR5## or a salt, N-oxide or acyl derivativethereof, wherein R², R⁹ and R¹⁰ are as hereinbefore defined and R¹³ ishydrogen, halogen, C₁₋₃ alkylthio C₁₋₃ alkyl or C₁₋₃ alkoxy optionallysubstituted by halogen, hydroxy or C₁₋₂ alkoxy, except that when R², R⁹and R¹³ are all hydrogen, R¹⁰ is neither hydrogen nor hydroxy. SuitablyR⁹ is hydrogen, methoxy, ethoxy, mono-C₁₋₃ -alkylamino, C₂₋₃ alkenyl,C₁₋₃ alkyl or methylthio. Most suitably R⁹ is hydrogen, methoxy, ethoxy,or methylthio. Preferably R⁹ is hydrogen, methoxy or ethoxy.

Suitably R¹⁰ is hydrogen, methoxy, ethoxy, methylthio, or a group NR¹³R¹⁴ as hereinbefore defined. Most suitably R¹⁰ is methoxy, ethoxy, aminoor dimethylamino. Preferably R¹⁰ is methoxy, ethoxy or amino.

Suitably R² is hydrogen, alkylthio, methoxy, ethoxy or methoxyethoxy.Preferably R² is hydrogen or methoxy.

Suitably R¹³ is hydrogen, methylthio or methoxy and preferably R¹³ ishydrogen or methoxy.

Preferred compounds of the present invention include:

2,4-diamino-5-(4-methoxy-1-naphthylmethyl)pyrimidine,

2,4-diamino-5-(4-amino-3-methoxy-1-naphthylmethyl)pyrimidine,

2,4-diamino-5-(4-hydroxy-3-methoxy-1-naphthylmethyl)pyrimidine,

2,4-diamino-5-(3,4-dimethoxy-1-naphthylmethyl)pyrimidine,

2,4-diamino-5-(4-amino-3,6-dimethoxy-1-naphthylmethyl)pyrimidine, or asalt, N-oxide or acyl derivative thereof.

Suitably the compounds of the formula (II) to (IV) are present in theform of the free base or an acid addition salt thereof.

Certain compounds of the formula (II) whilst having some antibacterialactivity in their own right are also useful as intermediates in thepreparation of other compounds of the formula (II) having interestingantibacterial activity.

The compounds of the formula (II) are bases and, as such, form acidaddition salts with acids. Suitable acid addition salts of the compoundsof the formula (II) include those formed with both organic and inorganicacids. Such acid addition salts will normally be pharmaceuticallyacceptable. Thus, preferred salts include those formed fromhydrochloric, sulphuric, citric, tartaric, phosphoric, lactic, benzoic,glutamic, aspartic, pyruvic, acetic, succinic, fumaric, maleic,oxaloacetic, isethionic, stearic, fumaric, methanesulphonic, toluenep-sulphonic, lactobionic and glucuronic acids.

When the compounds of the formulas (II) to (IV) are substituted byhydroxy groups, alkali metal salts of these compounds may be formed andthese salts also comprise part of the present invention. Particularlysuitable alkali metal salts are those formed with sodium and potassium.

Suitable acyl derivatives are those wherein an amino group issubstituted by a group --COR¹⁴ wherein R¹⁴ is hydrogen or C₁₋₁₁ alkyl orC₂₋₁₁ alkenyl, preferably C₁₋₄ alkyl or C₂₋₄ alkenyl, optionallysubstituted by carboxy, carb-C₁₋₄ alkoxy, nitrile, amino, chlorine orphenoxy optionally substituted by halogen, methyl or methoxy, the alkylor alkenyl groups being optionally interspersed with one or more oxygenatoms or forming part or the whole of a cycloaliphatic ring or R¹⁴ mayrepresent a C₆₋₁₀ aromatic or C₆₋₁₀ araliphatic residue optionallysubstituted by one or more chlorine atoms or methyl, OCH₂ COOH,carb-C₁₋₄ alkoxy or a heterocyclic group containing one or morenitrogen, oxygen or sulphur atoms. Preferred acyl derivatives are thosewherein the amino group at the 2-position of the pyrimidine ring issubstituted, particularly those wherein the amino group is substitutedby acetyl or by an acyl group derived from an amino acid such as aglycyl group.

Suitable N-oxides of compounds of the formula (II) include those formedby oxidation of either or both of the nitrogen atoms in the pyrimidinering.

The preparation of salts, acyl derivatives and N-oxides is carried outby conventional methods well known to those skilled in the art.

Pharmaceutically acceptable acid addition salts of compounds of theformula (II) form a particularly preferred aspect of the presentinvention.

In a further aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the formula (II) in a combinationwith a pharmaceutically acceptable carrier. By the terms "pharmaceuticalcomposition" and "pharmaceutically acceptable carrier" are meant thosecompositions and carriers suitable for use in human and/or veterinarymedicine.

The compounds of the formula (II) can conveniently be presented in thecompositions of the present invention in an effective unit dosage form,that is to say in an amount sufficient to be effective against thebacterial organism in vivo.

The pharmaceutically acceptable carriers present in the compositions ofthe present invention are materials recommended for the purpose ofadministering the medicament. These may be liquid, solid or gaseousmaterials, which are otherwise inert or medically acceptable and arecompatible with the active ingredient.

These pharmaceutical compositions may be given parenterally, orally,used as a suppository, applied as an ophthalmic solution, or appliedtopically as an ointment, cream or powder. However, oral and parenteraladministration of the compositions is preferred for human use. Forveterinary use, intramammary as well as oral and parenteraladministration is preferred.

For oral administration, fine powders or granules will contain diluting,dispersing and/or surface active agents, and may be presented in adraught, in water or in a syrup, in capsules or cachets in the dry stateor in a non-aqueous suspension wherein suspending agents may beincluded, or in a suspension in water or syrup. Where desirable ornecessary, flavouring, preserving, suspending, thickening or emulsifyingagents can be included.

For parenteral administration, the compounds may be presented in sterileaqueous injection solutions which may contain antioxidants or buffers.

As stated above, free base or a salt thereof may be administered in itspure form unassociated with other additives in which case a capsule orcachet is the preferred carrier.

Other compounds which may be included are, for example, medically inertingredients, e.g. solid and liquid diluents such as lactose, glucose,starch of calcium phosphate for tablets or capsules; olive oil or ethyloleate for soft capsules; and water or vegetable oil for suspensions oremulsions; lubricating agents such as talc or magnesium stearate;gelling agents such as colloidal clays; thickening agents such as gumtragacanth or sodium alginate; and other therapeutically acceptableaccessory ingredients such as humectants, preservatives, buffers, andantioxidants which are useful as carriers in such formulations.

Alternatively the active compound may be presented in a pure form as aneffective unit dosage, for instance, compressed as a tablet or the like.

For veterinary use, different intramammary formulations will normally beprepared for use in dry cows and for use in milking cows. Thus,formulations for dry cow use will normally be in an oil, such as peanutoil, gelled with a gelling agent such as aluminium monostearate.Formulations for milking cow use will usually contain an emulsifyingagent (for example Tween 20 or a polysorbate) and a milk misciblecarrier such as peanut oil or a mineral oil.

It may be advantageous to include the compounds of formula (II) in apharmaceutical composition which includes other active ingredients forexample p-aminobenzoic acid competitors such as sulphonamides.

Of known p-aminobenzoic acid competitors, the following sulphonamidecompounds (or pharmaceutically acceptable salts thereof) areparticularly useful:

Sulfanilamide, Sulfadiazine, Sulfamethisazole, Sulfapyridine,Sulfathiazole, Sulfamerazine, Sulfamethazine, Sulfisoxazole,Sulformethoxine, 2-(p-Aminobenzene)sulfonamide-3-methoxypyrazine(Kelfizina), Sulfonyldianiline, Mafenide, 5-Sulfanilamido-2,4-dimethylpyrimidine, 4-(N¹ -Acetylsulfanilamido)-5,6-dimethoxy pyrimidine,3-Sulfanilamido-4,5-dimethyl isoxazole,4-Sulfanilamido-5-methoxy-6-decyloxy pyrimidine sulfamono-methoxine,4-p-(8-Hydroxy quinolinyl-4-azo)-phenylsulfanilamido-5,6-dimethoxypyrimidine, Sulfadimethoxine, Sulfadimidine, Sulfamethoxazole,Sulfamoxole, Sulfadoxine, Sulfaguanidine, Sulfathiodimethoxine,Sulfaquinoxaline, and p-(2-Methyl-8-hydroxyquinolinyl-5-azo)phenylsulfanilamido-5,6-dimethoxy pyrimidine.

However, the most preferred combinations include those containingSulfadizine, Sulfamethoxazole, Sulfadoxine, Sulfamoxole orSulfadimidine. The ratio of the compound of the formula (II) tosulphonamide will normally be from 3:1 to 1:10, for example 1:1 to 1:5.A particularly preferred composition of the present invention comprisesa compound of formula (II) and a sulphonamide in a ratio of 1:2 to 1:5preferably together with a pharmaceutically acceptable carrier.

Tablets or other forms of presentation provided in discrete units mayconveniently contain an amount of compound of the formula (II) which iseffective at a dosage or as a multiple of the same, for instance forhuman use, units containing 2.5 to 200 mg usually around 30 to 100 mg,for veterinary use, units containing 30 to 500 mg.

The pharmaceutical compositions of the present invention can be preparedby the admixture of a compound of the formula (II) with apharmaceutically acceptable carrier. Other active ingredients, such as asulfonamide, or conventional pharmaceutical excipients may be admixed asrequired.

The compounds of the present invention are useful for the treatment ofgram negative aerobic, gram positive aerobic or anaerobic bacterialinfections in mammals. They are particularly useful in the treatment ofStaphylococcal infections for example mastitis in cattle. Neisseriainfections in humans, for example N. gonorrhea, acne in humans, andanaerobic infections. Most compounds also have an excellent level ofgeneral antibacterial activity.

Still another aspect of the present invention provides a method for thetreatment or prophylaxis of bacterial infections in mammals by theadministration of an effective non-toxic antibacterial amount of acompound of formula (II) or a pharmaceutically acceptable salt thereof,or a composition as hereinbefore described.

As indicated above, the compounds of the formula (II) are generallyuseful in treating bacterial infections by rectal, parenteral, topicalor oral administration. The compounds of formula (II) are normallyadministered at a dose from 0.1 mg/kg to 30 mg/kg per day and preferably1 mg/kg to 10 mg/kg. The dose range for adult humans is generally from25 to 300 mg/kg and preferably 100 to 200 mg/day.

The dose range for intramammary administration of the compounds of theformula (II) is generally from 100 to 500 mg, preferably 200 mg to 400mg, per quarter of the udder to dry cows. Milking cows will normallyreceive four to six medications of a composition of the presentinvention, a dose being conveniently administered at milking time (i.e.twice daily) to each of the desired quarters of the udder. Dry cows willnormally receive only one medication of a composition of the presentinvention, one dose being provided to each of the four quarters of theudder.

The compounds of formula (II) and their pharmaceutically acceptablesalts may be prepared by methods known for the synthesis of compounds ofanalogous structure.

Thus the present invention provides a process for preparation ofcompounds of the formula (II) as hereinbefore defined which processcomprises:

(a) (i) the reaction of a guanidine salt with a compound of the formula(V) or (VI): ##STR6## wherein R¹ to R⁴ and the dotted lines are ashereinbefore defined, R¹⁵ is a C₁₋₄ alkyl group and R¹⁶ is anucleophilic leaving group such as a C₁₋₄ alkoxy group or an amino, C₁₋₄alkylamino, benzylamino, di-(C₁₋₄)alkylamino, naphthylamino, optionallysubstituted anilino, morpholino, piperidino or N-methyl piperazino groupand most preferably R¹⁶ is an anilino group:

(ii) the reaction of a compound of the formula (VII): ##STR7## whereinR¹ to R⁴, R¹⁵ and the dotted lines are as hereinbefore defined and R¹⁷is an alkoxycarbonyl or aldehyde group, with potassium or sodiumhydroxide in C₁₋₄ alkanol followed by addition of guanidine;

(iii) the reaction of a compound of the formula (VIII): ##STR8## whereinR¹⁸ is an amino group or a leaving group, such as a C₁₋₄ alkylthio groupor a halogen atom, R¹⁹ is a hydrogen or halogen atom, except that bothgroups R¹⁸ cannot be amino groups and R¹ to R⁴ and the dotted lines areas hereinbefore defined with an aminating agent such as ammonia andthereafter when R¹⁹ is a halogen atom removing this by hydrogenolysis;

(iv) the reaction of a compound of the formula (IX): ##STR9## wherein Zis a halogen atom and R¹ to R₄ and the dotted lines are as hereinbeforedefined or Z is hydroxy or di-C₁₋₄ alkyl substituted amino, R⁴ ishydroxy, amino, or mono- or di-C₁₋₄ alkyl substituted amino and R³, R¹and R² are as hereinbefore defined, with a compound of formula (X):##STR10## wherein T is a hydroxy or C₁₋₄ alkylthio group, and thenconverting the group T to hydrogen by hydrogenolysis when T is a C₁₋₄alkylthio group or, when T is a hydroxy group, by first converting it tothe mesylate or tosylate derivative or to thio, alkylthio or halogen andthen removing this by hydrogenolysis;

(b) when it is required to prepare a compound of the formula (II)wherein the 4-position of the phenyl ring is substituted by hydroxy,amino or substituted amino the reaction of a compound of the formula(XI): ##STR11## wherein R⁴ is hydroxy, amino, substituted amino and R¹and R³ and the dotted lines are as hereinbefore defined, with2,4-diamino-5-hydroxymethylpyrimidine;

(c) the conversion of one compound of the formula (II) to a differentcompound of the formula (II), for example by the

conversion of a hydroxy group to a C₁₋₄ alkylthio group or an optionallysubstituted C₁₋₄ alkoxy group or conversion of an amino group to a C₁₋₄alkylthio group or hydrogen, halogen, hydroxy or cyano via a diazo groupor to a substituted amino group by methods well known to those skilledin the art.

The reaction of guanidine with a compound of the formula (V) or (VI)will take place under conditions analogous to those described in U.K.Pat. Nos. 1 133 766 and 1 261 455 respectively for the preparation ofstructurally related benzylpyrimidines. Conveniently the reaction iscarried out in a C₁₋₄ alkanol, for example methanol or ethanol. Thecompounds of the formula (V) and (VI) may be prepared by methods knownin the art.

The reaction of a compound of the formula (VII) with guanidine and thepreparation of the compounds of the formula (VII) will be carried out bymethods analogous to those described in Belgian Patent No. 855 505.

In the compounds of the formula (VIII) when R¹⁸ or R¹⁹ are halogen atomsthese are suitably chlorine or bromine atoms. The reaction mayconveniently be carried out under the reaction conditions described inU.K. Pat. Nos. 875 562 and 1 132 082. The reduction of R¹⁹ when this ishalogen will suitably be carried out under the conditions described inGerman Offenlegungschrift 2258238. This is not a preferred method forpreparing those compounds wherein R³ or R⁴ are groups that aresusceptible to catalytic hydrogenation.

The compounds of formula (VIII) may be prepared by methods known in theart, for example as described in U.K. Pat. Nos. 875562 and 1132082 orGerman Offenlegungschrift No. 2258238. The compounds of the formula(VIII) wherein R¹⁸ and/or R¹⁹ are halogen atoms may conveniently beprepared from the corresponding compounds wherein R¹⁸ and/or R¹⁹ arehydroxy. These compounds may be prepared by methods analogous to thesedescribed in the art or by the reaction of a compound of the formula(XI) with 5-dimethylamino-methyluracil. This reaction will normally becarried out in an inert high boiling polar solvent, for example a highboiling C₂₋₆ alkanol such as ethylene glycol, at between 100° and 200°C. for example between 130° and 160° C. The reaction will normally becarried out under basic conditions when the 4-position of the phenylring is substituted by hydroxy, for example in the presence of sodiummethoxide, and under neutral conditions when the 4-position of thephenyl ring is substituted by amino or substituted amino. Compounds ofthe formula (VIII) wherein R⁴ is a hydroxy group may be converted tocompounds of the formula (VIII) wherein R⁴ is an alkoxy or C₁₋₄alkylthio group and compounds of the formula (VIII) wherein R⁴ is anamino group may be converted to compounds of the formula (VIII) whereinR⁴ is a C₁₋₄ alkylthio or substituted amino group or hydrogen by methodswell known to those skilled in the art.

Suitably Z is a dialkylamino or cyclic amino group containing up to 10carbon atoms; a dimethylamino group is particularly convenient. Thereaction will be carried out under conditions well known to thoseskilled in the art of Mannich reactions. It has been found that thereaction may suitably be carried out at an elevated temperature,suitably between 100° and 200° C. in a solvent having a suitably highboiling point, for example a glycol such as ethylene glycol. Thedethiation is suitably carried out by hydrogenolysis in the presence ofa transition metal catalyst; Raney nickel is particularly suitable forthis purpose. This reaction will normally be carried out in a polarsolvent, for example a C₁₋₄ alkanol such as methanol or ethanol.

Again, this is not a preferred method of preparing those compounds ofthe formula (II) wherein there are groups that are susceptible to acatalytic hydrogenation.

The reaction of a compound of the formula (XI) with2,4-diamino-5-hydroxymethyl pyrimidine will normally be carried outunder the reaction conditions described in U.K. Pat. No. 1413471. Thusthe reaction will conveniently be carried out in a polar non-phenolicsolvent capable of dissolving both reactants at a non-extremetemperature, for example between 50° C. and 150° C. The reaction ispreferably carried out in the presence of a strong acid catalyst, suchas hydrochloric, acetic, methane sulphonic or toluene-p-sulphonic acids.

It will be apparent to those skilled in the art that when certain ringsubstituents (R³ and R⁴) are present in the final compounds of theformula (II) certain methods of preparation will preferably not be usedto make these compounds due to the possibility of the reactionconditions changing the final product group.

The intermediates of the formula (V) to (VIII) are novel and as suchform a further aspect of the present invention.

In yet another aspect, the present invention provides the first use ofthe compounds of the formula (II) in human and veterinary medicine. Thepreferred human use of the compounds of the formula (II) is in thetreatment of prophylaxis of bacterial infections.

The following examples illustrate the preparation of the compounds ofthe present invention and their pharmacological properties. Alltemperatures are in degrees centigrade.

Pharmacological data

The compounds of the present invention were subjected to standard testsin order to determine the minimum inhibitory concentration in μg/mlneeded to inhibit a range of bacterial microorganisms in-vitro.

    ______________________________________                                        Compound                                                                      ______________________________________                                        TMP      2,4-Diamino-5-(3,4,5-trimethoxybenzyl)-                                       pyrimidine                                                           1        2,4-Diamino-5-(4-methoxy-1-naphthylmethyl)-                                   pyrimidine hydrochloride                                             2        2,4-Diamino-5-(4-amino-3,6-dimethoxy-1-naphthyl-                              methyl)pyrimidine                                                    3        2,4-Diamino-5-(4-hydroxy-3-methoxy-1-napthyl-                                 methyl)pyrimidine                                                    4        2,4-Diamino-5-(3,4-dimethoxy-1-naphthylmethyl)-                               pyrimidine                                                           5        2,4-Diamino-5-(α-naphthylmethyl)pyrimidine                     6        2,4-Diamino-5-(4-amino-3-methoxy-1-naphthyl-                                  methyl)pyrimidine                                                    ______________________________________                                    

EXAMPLE 1

A. 3-Anilino-2-(4-methoxy-1-naphthylmethyl)acrylonitrile

To a solution of 4-methoxy-1-naphthaldehyde (10.0 g, 53.7 mmol) and3-anilinopropionitrile (9.0 g, 61.6 mmol) in dimethylsulfoxide (25 mL)was added a solution of sodium methoxide (2.9 g, 53.6 mmol) in methanol(25 mL). The resulting mixture was heated to 133° with distillation ofthe methanol over 45 min. The reaction was then cooled, diluted withethanol:water and the precipitate that formed was collected, washed withwater, ethanol and hexane to give the title compound (10.28 g, 61%); mp188°-189° after recrystallization from 2-methoxyethanol. Anal. Calcd forC₂₁ H₁₈ N₂ O: C, 80.23; H, 5.77; N, 8.91. Found: C, 79.80; H, 5.74; N,8.87.

B. 2,4-Diamino-5-(4-methoxy-1-naphthylmethyl)pyrimidine hydrochloride

To 65 mL of ethanolic guanidine solution prepared from 3.42 g (35.8mmol) of guanidine hydrochloride and 2.00 g (37.0 mmol) of sodiummethoxide was added 9.00 g (28.6 mmol) of3-anilino-2-(4-methoxy-1-naphthylmethyl)acrylonitrile. The solution washeated under reflux for 1.5 hr, and then 60 mL of 2-methoxyethanol wasadded. The internal temperature was allowed to gradually increase to108° by distillation of the ethanol, after which it was heated at thistemperature for 2.5 hr. The hot mixture was filtered, and theprecipitate (7.04 g, 87% of crude product) recrystallized from 30%ethanol in the presence of hydrochloric acid, to give the titlecompound; mp 312°-314° dec. Anal. Calcd for C₁₆ H₁₆ N₄ O.HCl: C, 60.66;H, 5.41; N, 17.69; Cl, 11.19. Found: C, 60.67; H, 5.45; N, 17.70; Cl,11.19.

EXAMPLE 2

A. 2,4-Diamino-5-(4-hydroxy-3-methoxy-1-naphthylmethyl)pyrimidine

The formate of 2-methoxy-1-naphthol (J. E. Oatis, Jr., M. P. Russell, D.R. Knapp and T. Walle, J. Med. Chem. 1981, 24, 309) (7.23 g, 30.3 mmol),2,4-diamino-5-hydroxymethylpyrimidine (4.35 g, 30.3 mmol), concentratedhydrochloric acid (4.2 mL) and glacial acetic acid (60 mL) were refluxed2 hr. The resulting dark solution was evaporated to dryness and theresidue dissolved in water and neutralized with ammonia. The resultingtan precipitate (5.2 g) was recrystallized from aqueous ethanolcontaining a slight excess of hydrochloric acid to give title compoundas tan powder (2.83 g, 28%); mp ca. 290°-300° dec. Anal. Calcd for C₁₆H₁₆ N₄ O₂.HCl: C, 57.75; H, 5.15; N, 16.84; Cl, 10.65. Found: C, 57.62;N, 5.21; N, 16.79; Cl, 10.61.

B. 2,4-Diamino-5-(3,4-dimethoxy-1-naphthylmethyl)pyrimidine

To a solution of the product of Example 41A (1.37 g, 4.12 mmol) indimethyl sulfoxide (15 mL) was added potassium-t-butoxide (0.973 g, 8.24mmol) followed by methyl iodide (620 mg, 4.12 mmol). After 30 min, water(25 mL) was added and the resulting precipitate chromatographed onsilica gel eluted with methanolmethylene chloride (1:20). The titlecompound crystallized from ethanol as white granules (0.60 g, 47%); mp228°-230°. Anal. Calcd for C₁₇ H₁₈ N₄ O₂ : C, 65.79; H, 5.85; N, 18.05.Found: C, 65.70; H, 5.90; N, 18.04.

EXAMPLE 32,4-Diamino-5-(4-amino-3,6-dimethoxy-1-naphthylmethyl)pyrimidinedihydrochloride

A mixture of 1-amino-2,7-dimethoxynaphthalene (2.03 g, 10.00 mmol) [O.Fischer and W. Kern, J. Prakt. Chem., 94, 34(1916)],2,4-diamino-5-hydroxymethylpyrimidine (1.40 g, 10.0 mmol), glacialacetic acid (20 mL) and concentrated hydrochloric acid (1.4 mL) wasrefluxed for 2 hr. The cooled reaction mixture was diluted with acetoneand the resulting precipitate was collected and dried giving the titlecompound as a grey solid (3.40 g, 78%). Recrystallization from aqueousethanol with concentrated HCl gave an analytical sample, mp >210° dec.Anal. Calcd for C₁₇ H₁₉ N₅ O₂.2HCl.2H₂ O: C, 47.01; H, 5.80; N, 16.12;Cl, 16.32. Found: C, 47.19; H, 5.90; N, 16.05; Cl, 16.37.

EXAMPLE 4 2,4-Diamino-5-(4-amino-3-methoxy-1-naphthylmethyl)pyrimidinedihydro chloride

2-Methoxy-1-nitronaphthalene (E. Baltazzi, Compt. rend. 1950, 230, 2207)(7.00 g, 34.4 mmol) was reduced to 1-amino-2-methoxynaphthalene [10%Pd-C (0.7 g), ethanol (200 mL), H₂ (50 psi)] and immediately refluxedwith 2,4-diamino-5-hydroxymethylpyrimidine (4.82 g, 34.4 mmol) inglacial acetic acid (60 mL)-concentrated hydrochloric acid (5.7 mL).After 2 hr, the mixture was cooled and white solid (10.2 g) filteredoff. Recrystallization from 95% ethanol gave title compound as whitesolid (8.06 g, 62% from 2-methoxy-1-nitronaphthalene); mp 232°-234° dec.Anal. Calcd for C₁₆ H₁₇ N₅ O.2HCl.0.6H₂ O: C, 50.70; H, 5.37; N, 18.47;Cl, 18.71. Found: C, 50.78; H, 5.37; N, 18.48; Cl, 18.73.

EXAMPLE 5 Biological Data

                  (A) MIC TABLE 1                                                 ______________________________________                                                        Minimum Inhibitory                                                            Concentrations                                                                (μg/ml) of selected compounds                              Organisms         TMP       4      5                                          ______________________________________                                        St. faecalis CN478                                                                              0.1       0.05   1.0                                        St. agalactiae CN1143                                                                           0.5       0.5    1.0                                        Staph. aureus CN491                                                                             0.5       0.05   3.0                                        Vibrio cholerae ATCC14035                                                                       0.5       0.05   3.0                                        Esch. coli CN314  0.05      0.5    3.0                                        Pr. mirabilis S2409                                                                             5.0       10     100                                        Meningococci (average                                                                           18.0      1.1    --                                         5 strains)                                                                    Gonococci (average                                                                              37.1      2.0    --                                         17 strains)                                                                   B. fragilis (average                                                                            4.0       0.7    --                                         3-10 strains)                                                                 ______________________________________                                    

                  (B) MIC TABLE 2                                                 ______________________________________                                                     MIC (μg/ml)                                                   Compound     vs Staph. aureus                                                 ______________________________________                                        TMP          0.5                                                              1            1.0                                                              2            0.05                                                             3            0.05                                                             6            0.05                                                             ______________________________________                                    

EXAMPLE 6 Tablets

    ______________________________________                                                        Amount per tablet (mg)                                                          Single         Combi-                                       Ingredient        Active Ingredient                                                                            nation                                       ______________________________________                                        2,4-Diamino-5-(3,4-dimethoxy-1-                                                                 100.0          80.0                                         naphthylmethyl)pyrimidine                                                     Sulfamethoxazole  --             400.0                                        Lactose           84.0           100.0                                        Potato starch, dried                                                                            14.3           18.0                                         Magnesium stearate                                                                              0.7            1.0                                          Polyvinylpyrrolidone                                                                            1.0            1.0                                          ______________________________________                                    

The 2,4-diamino-5-(3,4-dimethoxy-1-naphthylmethyl)pyrimidine, lactoseand potato starch (and sulfamethoxazole in the combination formulation)are mixed together and then granulated with aqueous polyvinylpyrolidone.The granules are dried, mixed with the magnesium stearate and thencompressed to produce tablets weighing 200 mg each (single activeingredient) or 600 mg each (combination).

EXAMPLE 7 Veterinary Formulation

Syringes for intra-mammary injection into cows are prepared from thefollowing ingredients:

    ______________________________________                                        2,4-Diamino-5-(3,4-dimethoxy-1-naphthylmethyl)-                                                         3.75%   w/w                                         pyrimidine                                                                    Sulfadiazine              7.50%   w/w                                         Glycerol monostearate     9.50%   w/w                                         Tween 65                  0.50%   w/w                                         Arachis oil               78.75%  w/w                                         ______________________________________                                    

The glycerol monostearate, Tween 65 (a polyethylene oxide sorbitantristearate) and arachis oil are mixed together and melted at 65° C. Theactive ingredients(2,4-diamino-5-(3,4-dimethoxy-1-naphthylmethyl)pyrimidine andsulfadiazine) are mixed in and the mixture homogenized using a highspeed stirrer. The resulting mixture is cooled to 50° C. and is filledinto intra-mammary syringes using a fill weight of 4.0 g±5%. Themanufacture and filling operations are carried out under sterileconditions.

I claim:
 1. A compound of the formula ##STR12## wherein the dotted linesare both single bonds, R¹⁸ is amino or C₁₋₄ althylthio or halogen,R¹⁹ ishydrogen or halogen provided that both R¹⁸ groups cannot be amino, R¹and R² is hydrogen or halogen, C₁₋₄ alkyl, C₁₋₄ alkylthio, C₁₋₄ alkoxyand R³ and R⁴ are hydrogen, halogen, C₂₋₄ alkenyl, C₂₋₄ alkenyloxy,nitro, cyano, hydroxy or mercapto except that R¹ to R₄ may not all behydrogen and when R¹, R² and R³ are hydrogen, R⁴ may not be hydroxyl.